Many lipids are amphiphilic substances having hydrophilic and hydrophobic groups in the same molecules (hereafter referred to as “amphiphilic lipid(s)”) and spontaneously form molecular assemblies of various shapes in water. Representative examples of amphiphilic lipids include: synthetic surfactants, soaps, naturally occurring complex lipids such as lecithin, and block copolymers having hydrophobic and hydrophilic chains.
Amphiphilic lipids form molecular assemblies of various shapes in water at the Krafft temperature (TK; it may also be referred to as the “Krafft eutectic temperature”, “Krafft point” or the like) or higher, determined depending on the type or concentration of the lipid (see, Laughlin, R. G., “The Aqueous Phase Behavior of Surfactants,” 1994, Academic Press, London, pp. 106-117). Examples of such molecular assemblies include closed micelles with outward-directed hydrophilic groups (e.g., spherical micelles or rod-like micelles), closed inverted micelles with outward-directed hydrophobic groups, sponge phases comprising randomly continuous bilayers in which two hydrophobic groups or two hydrophilic groups of the amphiphilic lipid are arranged opposite each other, and various lyotropic liquid crystal phases. Known examples of lyotropic liquid crystal phases are hexagonal liquid crystals and inverted hexagonal liquid crystals in which cylindrical assemblies of unlimited lengths form two-dimensional hexagonal lattices, lamellar liquid crystals in which bilayer sheets are laminated at constant intervals in a Z-axis direction, cubic liquid crystals having three-dimensional lattice structures, and the like.
These molecular assemblies are put to various applications in fields relating to, for example, cosmetic and pharmaceutical products. For example, development of a drug delivery system (DDS) utilizing amphiphilic lipid is very active, and many forms of drug delivery carriers have been produced (see, JP Patent Publication (kohyo) No. 2002-505307 A and JP Patent Publication (kokai) No. 2001-231845 A), including a drug delivery system comprising drugs embedded in an aqueous phase or lipid bilayer of a liposome prepared from lamellar liquid crystals (see, Lasic D. D., TIBTECH 16, 1998, pp. 307-321).
Among molecular assemblies, bicontinuous cubic liquid crystals (which will be described in 1-(1) below) have unique liquid crystal structures-comprising water (or an aqueous medium) portions with diameters of the order of nm scale, which are in communication with the outside (hereafter referred to as “water channel(s)”), and curved lipid bilayers. Accordingly, bicontinuous cubic liquid crystals are capable of embedding greater amounts of both fat-soluble drugs and water-soluble drugs, they have more stable structures, and they have greater mechanical strength than liposomes or micelles. Further, cubic liquid crystals are capable of incorporating water-soluble proteins in water channels and hydrophobic membrane proteins in lipid bilayers. Thus, cubic liquid crystals have drawn attention as novel drug delivery carriers that differ from liposomes or micelles (Engstrom, S., Lipid Technol. 2, 1990, pp. 42-45; Shah, J. C., et al., Adv. Drug Delivery Reviews 47, 2001, pp. 229-**250; Ganem-Quintanar, A., Quintanar-Guerrero, D., and Buri, P., Drug Development and Industrial Pharmacy, 26(8), 2000, pp. 809-820; and Drummond, C. J. and Fong, C., “Surfactant self-assembly objects as novel drug delivery vehicles.” Curr. Opin. Colloid Interface Sci., 4, 2000, pp. 449-456).
A majority of cubic liquid crystals found in an amphiphilic lipid/water system can remain stable only in a narrow concentration range between other phase regions, such as aqueous micelle solution, hexagonal liquid crystals, lamellar liquid crystals, and inverted hexagonal liquid crystals that account for the wide area of a phase diagram for a two-component system of amphiphilic lipid/water (Fontell, K. Colloid & Polymer Sci., 268, 1990, pp. 264-285). Thus, use of cubic liquid crystals as drug delivery carriers or the like has difficulty. Since cubic liquid crystals of monoacylglycerols such as monoolein or phytantriol (Barauskas, J., Landh, T., Langmuir, 2003, 19, pp. 9562-9565) are “type II cubic liquid crystals” (described below) wherein a cubic phase is adjacent to an aqueous phase on a phase diagram for the two-component system of amphiphilic lipid/water, they are relatively stable in the presence of excess water. Thus, application thereof for a drug delivery system or the like has been attempted. Cubic liquid crystals of phytantriol are transformed into inverted hexagonal liquid crystals at about 40° C. or higher, and therefore the stability thereof is problematic in high-temperature regions. Further, upon embedding of fat-soluble drugs such as vitamin A therein, maintenance of the cubic liquid crystal structure of phytantriol has become difficult. Among the aforementioned monoacylglycerols, the Krafft temperatures of monomyristolein, monopentadecenoin, and monooctadecanoin, for example, are as high as 35° C. (Briggs, J. Caffrey, M. Biophys. J., 66, 1994, pp. 573-587), 30° C. (Briggs, J. Caffrey, M. Biophys. J., 67, 1994, pp. 1594-1602), and 80° C. (Lutton E. S., J. Am. Oil Chem. Soc., 42, 1965, pp. 1068-1070), and they cannot form cubic liquid crystals at room temperature. Thus, such substances are not suitable for drug delivery carriers. In contrast, the Krafft temperature of monoolein or monovaccenin having unsaturated fatty acid in a hydrophobic chain is as low as 15° C. (Qiu, H., and Caffrey, M., Biomaterials 21, 2000, pp. 223-234; Qui, H., Caffrey, M., J. Phys. Chem. B. 102, 1998, pp. 4819-4829). It is no exaggeration to say that conventional studies concerning drug delivery systems or the like utilizing cubic liquid crystals have been limited to cubic liquid crystals of monoolein (U.S. Pat. Nos. 5,531,925; 5,196,201; 6,656,385; 5,143,934; 5,593,663; 5,756,108; JP Patent Publication (kohyo) No. 2004-502524; Drummond, C. J. and Fong, C., “Surfactant self-assembly objects as novel drug delivery vehicles.” Curr. Opin. Colloid Interface Sci., 4, 2000, pp. 449-456). However, monoolein is susceptible to oxidation, and it cannot remain stable due to rapid enzymatic degradation into fatty acid and glycerine in the blood (Leesajakul, W., Nakano, M., Taniguchi, A., Handa, T., Colloid Surf., B., 2004, pp. 253-258). In addition, it disadvantageously becomes unstable when stored at refrigeration temperatures (lower than 6° C.) or subjected to experimentation at such temperatures.
In the past, therefore, the present inventors developed glycolipids having isoprenoid-type hydrophobic chains having relatively low Krafft temperatures (JP Patent Publication (kokai) No. 8-245682 A; JP Patent Publication (kokai) No. 2002-226497 A). Among such glycolipids, 1-O-(3,7,11,15-tetramethylhexadecyl)-β-D-xyloside formed cubic liquid crystals in the presence of water, and the Krafft temperature thereof was 10° C. (Hato, M., Minamikawa, H., Salkar, R. A., Matsutani, S. Langmuir, 18 (2002) pp. 3425-3429; Hato, M., Minamikawa, H., Salkar, R. A., Matsutani, S. Progr. Colloid Polym. Sci., 123 (2004) pp. 56-60; Hato, M., Yamashita, I., Kato, T., Abe Y., Langmuir, (2004) 20, pp. 11366-11373). In recent years, a lipid that has a Krafft temperature of 6° C. and belongs to monoacylglycerols has been reported (Mesquitta, Y., Cherezov, V., Havas, F., Patterson, S., Mohan, J. M., Wells, A. J., Hart, D. J., Caffrey, M., J. Structural Biol., (2004) 148, pp. 169-175). However, such lipids are not suitable for storage or experimentation at refrigeration temperatures (about 4° C.) or lower, and improvement is required.